SUMMARY/ABSTRACT Human autoimmune diseases such as type 1 diabetes (T1D) are characterized by heterogeneous and complex events driving immunopathology. To deal with this heterogeneity for disease prevention and treatment, we need a variety of immunotherapies with distinct mechanisms of action. With this in mind, the goal of our R21 proposal is to establish proof-of-concept that pulsed electromagnetic field (PEMF) therapy is an effective approach to selectively suppress ongoing autoimmunity, and reestablish self-tolerance. Micro/nano-currents induced in vivo by PEMF under the appropriate conditions can alter cellular properties. Different types of PEMF have been successfully and safely applied in the clinic; however, use of PEMF for autoimmunity has not been tested. For this study, we are using a unique type of PEMF referred to as inductively coupled electrical stimulation (ICES). Properties of ICES result in electromagnetic pulses believed to closely mimic native electrical signaling events that enhance both biological effects and safety. Three Aims are outlined, employing NOD mice a spontaneous model of T1D, to establish the applicability of ICES-based PEMF to modulate autoimmunity. In Aim 1, studies will define the tolerogenic effects of ICES on ? cell-specific T cell reactivity. Aim 2 will focus on determining ICES effects on dendritic cell maturation and function. In Aim 3 ICES-induced immunoregulation will be explored, and effects on acquired immunity investigated. This work is expected to establish a foundation for future studies: 1) to further define the mechanisms by which ICES specifically, and PEMF in general regulate immune effectors, and 2) to test the clinical application of ICES to prevent and/or treat T1D, as well as other autoimmune diseases and immune-driven pathologies.